1. Field of the Invention
The invention relates generally to a reproducible, efficient method of preparing nonaggregated microcapsules suitable for encapsulation of diagnostic and therapeutic agents. The invention also relates to methods of use for encapsulated diagnostic and therapeutic agents and in particular aspects to the use of amino acid conjugated polymers as microencapsulation materials. Conjugated amino acid ester microencapsulated agents have particular potential for drug targeting.
______________________________________ LIST OF ABBREVIATIONS ______________________________________ PLA poly-(D,L)-lactic acid PCL polycaprolactone PCLD polycaprolactone diol 5-FU 5-fluorouracil TX Tamoxifen EHEC ethylhydroxyethyl cellulose CDDP cisdiamminedichloroplatinum, (cisplatin) MAA macroaggregated albumin DTPA diethyltriaminepenta-acetic acid ______________________________________
2. Description of Related Art
Microencapsulation is a well-studied art. It is basically the use of a matrix or encapsulating material to enclose gases, liquids or solids into particles of relatively small size (0.5-500 .mu.m). The matrix is capsular material selected according to the intended use of the microcapsules.
Physical properties of encapsulated chemical entities may be modified because of the encapsulation. Other effects of encapsulation include dispersion of one substance within another, stabilization of emulsions and alteration of solubility rate. One of the most useful properties of encapsulated therapeutic materials is controlled release (1,2).
Microcapsules have been prepared by many methods, including coacervation, interfacial polymerization, mechanical methods, polymer dispersion and matrix encapsulation. Sustained release microcapsules have been prepared from ethylcellulose (3) and poly-(D,L)-lactide (4). There is voluminous literature on the preparation and use of encapsulating polymers designed for sustained drug release (5,6).
Although many preparations of microencapsulated compounds have been reported, few describe microparticles in the size range below 10 .mu.m. Particles of 1-250 .mu.m are typically prepared by a solvent evaporation technique (7) while sizes from 1-10 .mu.m have been made by emulsion deposition (8). One method using solvent evaporation claims to provide a range of sizes from 0.5-250 .mu.m (9). Nevertheless, none of these methods appears to provide a homogeneous preparation of single-particle, nonaggregated microcapsules. Typical of these preparations is a claim to aggregate having an overall size of about 177 to 395 .mu.m with 5-162 .mu.m particles making up the aggregates (10). This technique requires sieving to remove larger agglomerates, leaving behind a wide range of particle sizes which, although composed of small spheres, are nevertheless in aggregated form.
Discrete microprills, polymeric particles in which a drug (for example, Mellarib.TM.) is uniformly dispersed, have been disclosed (11). Although the microprills were reported to be nonaggregated, the average size range was 10-50 .mu.m.
Lack of particle size homogeneity may cause severe problems in quality control and in clinical use. For example, in chemoembolization studies, the particle diameter is fairly critical in that only a limited range of sizes will lodge in a target area (12). If too large, damage to larger vessels may occur, while if too small, the particles pass through and drug is not released at the targeted site. Thus a homogeneous particle preparation is important.
Despite the proliferation of microencapsulation methods, there is a particular need for simple and efficient methods of producing homogeneous preparations of microencapsulated agents for clinical treatment and diagnosis, most particularly in small, nonaggregated particles ranging from 0.5 to 500 .mu.m. A method of preparing encapsulated therapeutic agents in 1 .mu.m and 100 .mu.m particles would provide more effective agents, particularly for diagnostic imaging and chemoembolization.
Bioimaging agents microencapsulated in 1 .mu.m particles would provide an ideal size particle for bioimaging studies, particularly if combined with capsular material selected to concentrate in the organ of interest. Additionally, the use of microencapsulation materials capable of targeting particular areas in vivo would enable improvements in biodistribution imaging studies as well as in drug delivery to specific organs.